Continuous intravenous vancomycin in children with

doi: 10.1111/fcp.12344 ORIGINAL ARTICLE

Continuous intravenous vancomycin in children with normal renal function hospitalized in hematology–oncology: prospective validation of a dosing regimen optimizing steady-state concentration Delphine Hoegya,b,c* , Sylvain Goutelleb,d,e,f, Nathalie Garniera,b, Cecile Renarda,b, Cecile Faure-Contera,g, Christophe Bergerona,g, Yves Bertranda,b,e, Nathalie Bleyzaca,b,h a

Institut d’Hematologie et d’Oncologie Pediatrique, 1 Place Pr J. Renaut 69008, Lyon, France Hospices Civiles de Lyon, Lyon, France c EA4129, Laboratoire Parcours sante systemique, 7-9 rue G. Paradin 69008, Lyon, France d Laboratoire de Biometrie et Biologie Evolutive, UMR CNRS 5558, 43 bd du 11 novembre 1918 69622, Villeurbanne Cedex, France e Universite Lyon I, Villeurbanne, France f Pharmacie, Groupe Hospitalier Nord, Lyon, France g Centre Leon Berard, Lyon, France h EMR 3738 Optimisation Therapeutique en Oncologie et Onco-hematologie, Lyon, France b

Keywords cancer, continuous infusion, pediatrics, vancomycin

Received 22 July 2017; revised 16 December 2017; accepted 22 December 2017

*Correspondence and reprints: [email protected]

ABSTRACT

Continuous intravenous (IV) infusion has been shown to be the best option to administer vancomycin because of its time-dependent bactericidal activity. Available IV vancomycin dosing guidelines in pediatrics with normal renal function leads to less than 50% of patients achieving a vancomycin serum concentration (Css) in the target range (15–20 mg/L). The primary objective of this study was to prospectively validate an age-based dosing regimen in pediatric oncology–hematology. The secondary objective was to investigate the influence on Css attainment of different variables. A continuous IV dosing nomogram was built by retrospective study (2000–2010) on Bayesian dosing adjustments performed in 161 patients. This study assessed the prospective validation of this age-based nomogram and the influence on Css attainment of variables as the gender, underlying disease (oncology or hematology), and hematopoietic stem cell transplantation (HSCT) before receiving vancomycin therapy. A total of 94 patients aged from 4.3 months to 17.9 years old with normal renal function were eligible for the prospective validation. Fifty-five of those patients (58.5%) achieved the target range of vancomycin Css. There was no significant difference between age groups (P = 0.816) and no influence of gender (P = 0.500). There was a nonsignificant trend to a better target attainment in oncology patients (69.2% vs. hematology 54.4%, P = 0.142) and patients who did not undergo HSCT (63.3% vs. 33.3%, P = 0.031). This study proposed an age-based nomogram prospectively validated which near 60% of patients of each age class achieving the target range of Css.

te Francßaise de Pharmacologie et de The rapeutique ª 2018 Socie Fundamental & Clinical Pharmacology 32 (2018) 323–329

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INTRODUCTION Vancomycin is still one of the first-line agents for treatment of suspected infections in pediatric patients with febrile neutropenia and a central venous line. Achieving efficient plasma concentrations of vancomycin as soon as possible during vancomycin therapy is the most important for optimal response, considering the emergence resistance bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) [1]. The wide interindividual pharmacokinetic variability of vancomycin makes difficult the achievement of optimal plasma levels. The most widely used index of vancomycin drug exposure in routine therapeutic drug monitoring (TDM) is the trough concentration (Cmin) for intermittent administration and the steady-state concentration (Css) for continuous infusion [2–4]. According to the latest US guidelines [2], the optimal target is a ratio of area under the concentration–time curve (AUC) over the bacterial minimum inhibitory concentration (MIC) ≥ 400, for both intermittent and continuous IV. The guidelines recommend vancomycin Cmin of 15–20 mg/L for intermittent dosing, but no target has been clearly defined for continuous IV and Css [2]. Since then, it has been shown that Cmin values lower that 15 mg/L may be sufficient while 15– 20 mg/L is adequate for Css to achieve an AUC target of 400 [5–8]. Continuous intravenous (IV) infusion has been shown to be an effective way to administer vancomycin because of its time-dependent bactericidal activity [9–11]. However, there are still no dosing guidelines of continuous IV vancomycin in pediatric patients. The usual intermittent dosing regimen of 40 mg/kg/day (i.e., 10 mg/kg/6 h) leads to low serum concentrations, with more than 95% of patients below the target range [12]. In 2011, IDSA guidelines for the treatment of MRSA infections proposed to increase the dosage in pediatrics from 40 to 60 mg/kg/24 h divided into four daily doses [3]. It has been shown that the dosage of 60 mg/kg/ 24 h (i.e., 15 mg/kg/6 h) proposed by IDSA guidelines was associated with only 7–39% of patients with Cmin within the target range [13–18]. Some studies have suggested that doses as high as 70–85 mg/kg/day should be used in children to achieve the target exposure [15,16,18,19], but they did not provide any prospective validation data. Model-based simulations of these regimens have shown that only 40–50% of

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pediatric patient may achieve the target range of serum concentrations [20]. Zhao et al. [17] performed population pharmacokinetic analysis and dosing simulations of vancomycin in children with hematological malignancies. They compared weight-based dosing (90 mg/kg/day in infants and 80 mg/kg/day in older children) and model-based dosing in the achievement of target vancomycin exposure in simulated patients. The results showed that less than 30% of simulated patients achieved the Cmin range of 15-20 mg/L with both dosing approaches. In addition, a significant proportion of overexposure (Cmin > 20 mg/L) was observed (20% and 26% for model-based and weight-based dosing, respectively) [17]. The primary objective of our study was to prospectively validate an age-based dosing regimen for continuous IV vancomycin in a large cohort of children with normal renal function admitted to a hematology–oncology unit. The secondary objective of our study was to investigate the determinants of attainment of the concentration target range in this population. MATERIALS AND METHODS Design The dosing regimen of vancomycin was based on a retrospective study where Bayesian dosing adjustments were performed in children hospitalized in our hematology–oncology unit [21]. In this previous work, 161 patients, aged from 1 month to 18 years, treated with continuous IV vancomycin between 2000 and 2010, were studied. Inclusion criteria were normal renal clearance estimated by the Schwartz formula [22,23] before vancomycin administration and availability of measured vancomycin serum concentrations. In 2010, the initial dosage recommended was 40 mg/kg/day, and the objective was a steady-state concentration of vancomycin 48 h after starting the treatment (Css) within 15–20 mg/L. Each patient with a Css outside this objective range 48 h after the initial dose was subject to Bayesian individualization of dosage regimen using the USCPACK software [24]. Dosages necessary to reach a Css between 15 and 20 mg/L were then collected and analyzed using SPSS software (Table I). Those dosages were stratified into four groups according to patients’ age (Table I). Easier to use than a Bayesian program, those results were the new dosing recommendations from 2010 in our center where continuous IV


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vancomycin could be started 24/24 h and 7/7 days (Table I) [21]. From 2010, a prospective evaluation of those dosing recommendations stratified by age was carried out. Data were obtained from routine clinical care of patients, so no approval of any ethical committee was required, as authorized by French laws.

All statistical analyses were performed using SPSS software (17th version, SPSS Inc., Chicago, USA). The chi-squared test was used to compare the proportion of vancomycin-measured Css within the target range according to the class of age, gender, BMI, disease, and HSCT. Differences were considered as significant when the P-value was 800 mg h/L as independent predictors of nephrotoxicity, with oddsratio of 2.5 and 3.7, respectively [41]. As explained above, with continuous infusion of vancomycin, a Css of 15–20 mg/L is associated with an AUC value much lower than 800 mg h/L and therefore should be relatively safe. Data from adult patients have confirmed this point, as a higher vancomycin Css (≥28 mg/L) was associated with nephrotoxicity [42].

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CONCLUSION To conclude, a dosing regimen has been designed to achieve vancomycin Css of 15–20 mg/L in children with normal renal function hospitalized in hematology–oncology treated by continuous infusion. This dosing regimen has then been prospectively validated in 94 patients, showing a good rate of target attainment. It may now be recommended for use in clinical practice for early optimization of vancomycin exposure. ACKNOWLEDGEMENTS The authors declare that this work received no funding. Conflict of interest. The authors report no conflict of interests. ABBREVIATIONS BMI – body mass index Css – vancomycin serum concentration HSCT – hematopoietic stem cell transplantation IV – intravenous MRSA – methicillin-resistant Staphylococcus aureus REFERENCES 1 Appelbaum P.C. Reduced glycopeptide susceptibility in methicillin-resistant Staphylococcus aureus (MRSA). Int. J. Antimicrob. Agents (2007) 30 398–408. 2 Rybak M.J., Lomaestro B.M., Rotschafer J.C. et al. Vancomycin therapeutic guidelines: a summary of consensus recommendations from the infectious diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists. Clin. Infect. Dis. (2009) 49 325–327. 3 Liu C., Bayer A., Cosgrove S.E. et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin. Infect. Dis. (2011) 52 e18–e55. 4 Kullar R., Davis S.L., Levine D.P., Rybak M.J. Impact of vancomycin exposure on outcomes in patients with methicillin-resistant Staphylococcus aureus bacteremia: support for consensus guidelines suggested targets. Clin. Infect. Dis. (2011) 52 975–981. 5 Bel Kamel A., Bourguignon L., Marcos M., Ducher M., Goutelle S. Is trough concentration of vancomycin predictive of the area under the curve? A clinical study in elderly patients. Ther. Drug Monit. (2017) 39 83–87.

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6 Frymoyer A., Hersh A.L., El-Komy M.H. et al. Association between vancomycin trough concentration and area under the concentration-time curve in neonates. Antimicrob. Agents Chemother. (2014) 58 6454–6461. 7 Haeseker M., Croes S., Neef C. et al. Evaluation of vancomycin prediction methods based on estimated creatinine clearance or trough levels. Ther. Drug Monit. (2016) 38 120–126. 8 Le J., Bradley J.S., Murray W. et al. Improved vancomycin dosing in children using area under the curve exposure. Pediatr. Infect. Dis. J. (2013) 32 e155–e163. 9 James J.K., Palmer S.M., Levine D.P., Rybak M.J. Comparison of conventional dosing versus continuous-infusion vancomycin therapy for patients with suspected or documented gram-positive infections. Antimicrob. Agents Chemother. (1996) 40 696–700. 10 Kasiakou S.K., Michalopoulos A., Soteriades E.S., Falagas M.E. Continuous versus intermittent intravenous administration of antibiotics: a meta-analysis of randomised controlled trials. Lancet. Infect. Dis. (2005) 5 581–589. 11 Wysocki M., Delatour F., Faurisson F. et al. Continuous versus intermittent infusion of vancomycin in severe staphylococcal infections: prospective multicenter randomized study. Antimicrob. Agents Chemother. (2001) 45 2460–2467. 12 Nassar L., Hadad S., Gefen A. et al. Prospective evaluation of the dosing regimen of vancomycin in children of different weight categories. Curr. Drug. Saf. (2012) 7 375–381. 13 Demirjian A., Finkelstein Y., Nava-Ocampo A. et al. A randomized controlled trial of a vancomycin loading dose in children. Pediatr. Infect. Dis. J. (2013) 32 1217–1223. 14 Hwang D., Chiu N.C., Chang L. et al. Vancomycin dosing and target attainment in children. J. Microbiol. Immunol. Infect. (2017) 50 494–499. 15 EilandL S., English T.M., Eiland E.H. Assessment of vancomycin dosing and subsequent serum concentrations in pediatric patients. Ann. Pharmacother. (2011) 45 582–589. 16 Durham S.H., Simmons M.L., Mulherin D.W., Foland J.A. An evaluation of vancomycin dosing for complicated infections in pediatric patients. Hosp. Pediatr. (2015) 5 276–281. 17 Zhao W., Zhang D., Fakhoury M. et al. Population pharmacokinetics and dosing optimization of vancomycin in children with malignant hematological disease. Antimicrob. Agents Chemother. (2014) 58 3191–3199. 18 Hoang J., Dersch-Mills D., Bresee L., Kraft T., Vanderkooi O.G. Achieving therapeutic vancomycin levels in pediatric patients. Can. J. Hosp. Pharm. (2014) 67 416–422. 19 Abdel Hadi O., Al Omar S., Nazer L.H., Mubarak S., Le J. Vancomycin pharmacokinetics and predicted dosage requirements in pediatric cancer patients. J. Oncol. Pharm. Pract. (2016) 22 448–453. 20 Goutelle S., Neely M., Bleyzac N. Comment: assessment of vancomycin dosing and subsequent serum concentrations in pediatric patients. Ann. Pharmacother. (2011) 45 1171– 1172. 21 Zegbeh H., Bleyzac N., Berhoune C., Bertrand Y. Vancomycin: what dosages are needed to achieve efficacy in paediatric hematology/oncology? Arch. Pediatr. (2011) 18 850–855.


329

Dosing regimen of continuous vancomycin in children

22 Schwartz G.J., Haycock G.B., Edelmann C.M.J.R., Spitzer A. A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics (1976) 58 259–263. 23 Schwartz G.J., Work D.F. Measurement and estimation of GFR in children and adolescents. Clin. J. Am. Soc. Nephrol. (2009) 4 1832–1843. 24 Jelliffe R.W., Schumitzky A., Van Guilder M. et al. Individualizing drug dosage regimens: roles of population pharmacokinetic and dynamic models, Bayesian fitting, and adaptive control. Ther. Drug Monit. (1993) 15 380–393. 25 Usman M., Hempel G. Development and validation of an HPLC method for the determination of vancomycin in human plasma and its comparison with an immunoassay (PETINIA). Springerplus (2016) 5 124. 26 McNeil J.C., Hulten K.G., Kaplan S.L., Mahoney D.H., Mason E.O. Staphylococcus aureus infections in pediatric oncology patients: high rates of antimicrobial resistance, antiseptic tolerance and complications. Pediatr. Infect. Dis. J. (2013) 32 124–128. 27 Rodvold K.A., Everett J.A., Pryka R.D., Kraus D.M. Pharmacokinetics and administration regimens of vancomycin in neonates, infants and children. Clin. Pharmacokinet. (1997) 33 32–51. 28 Chang D. Influence of malignancy on the pharmacokinetics of vancomycin in infants and children. Pediatr. Infect. Dis. J. (1995) 14 667–673. 29 Krivoy N., Peleg S., Postovsky S., Ben Arush M.W. Pharmacokinetic analysis of vancomycin in steady state in pediatric cancer patients. Pediatr. Hematol. Oncol. (1998) 15 333–338. 30 Piro C.C., Crossno C.L., Collier A., Ho R., Koyama T., Frangoul H. Initial vancomycin dosing in pediatric oncology and stem cell transplant patients. J. Pediatr. Hematol. Oncol. (2009) 31 3–7. 31 Varani J., Ward P.A. Mechanisms of neutrophil-dependent and neutrophil-independent endothelial cell injury. Biol. Signals (1994) 3 1–14. 32 Samaniego F., Markham P.D., Gendelman R. et al. Vascular endothelial growth factor and basic fibroblast growth factor present in Kaposi’s sarcoma (KS) are induced by inflammatory cytokines and synergize to promote vascular


33

34

35

36

37

38

39

40

41

42

permeability and KS lesion development. Am. J. Pathol. (1998) 152 1433–1443. Rodieux F., Wilbaux M., Van den Anker J.N., Pfister M. Effect of kidney function on drug kinetics and dosing in neonates, infants, and children. Clin. Pharmacokinet. (2015) 54 1183– 1204. Buelga D.S., Fernandez M., Herrera E.V., Dominguez-Gil A., Garcıa M.J. Population pharmacokinetic analysis of vancomycin in patients with hematological malignancies. Antimicrob. Agents Chemother. (2005) 49 4934–4941. Eiland L.S., Sonawane K.B. Vancomycin dosing in healthyweight, overweight, and obese pediatric patients. J. Pediatr. Pharmacol. Ther. (2014) 19 182–188. Le J., Capparelli E.V., Wahid U. et al. Bayesian estimation of vancomycin pharmacokinetics in obese children: matched case-control study. Clin. Ther. (2015) 37 1340–1351. Moise-Broder P.A., Forrest A., Birmingham M.C., Schentag J.J. Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections. Clin. Pharmacokinet. (2004) 43 925–942. Men P., Li H.B., Zhai S.D., Zhao R.S. Association between the AUC0-24/MIC ratio of vancomycin and its clinical effectiveness: a systematic review and meta-analysis. PLoS ONE (2016) 11 e0146224. Neely M.N., Youn G., Jones B. et al. Are vancomycin trough concentrations adequate for optimal dosing? Antimicrob. Agents Chemother. (2014) 58 309–316. Downes K.J., Goldstein S.L., Vinks A.A. Increased vancomycin exposure and nephrotoxicity in children: therapeutic does not mean safe. J. Pediatric. Infect. Dis. Soc. (2016) 5 65–67. Le J., Ny P., Capparelli E. et al. Pharmacodynamic characteristics of nephrotoxicity associated with vancomycin use in children. J. Pediatric. Infect. Dis. Soc. (2015) 4 e109– e116. Ingram P.R., Lye D.C., Tambyah P.A., Goh W.P., Tam V.H., Fisher D.A. Risk factors for nephrotoxicity associated with continuous vancomycin infusion in outpatient parenteral antibiotic therapy. J. Antimicrob. Chemother. (2008) 62 168–171.